Cases in Biologic Therapeutic Drug MonitoringPresented by: Jane Yang, MD LabCorp Medical Science Director
June, 2019
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• 65 y/o female with 15-year history of seropositive RA. Treated for several years with DMARDs.
• Presented with persistent active inflammatory arthritis after failing traditional DMARDs.
• 3 years ago, started on adalimumab (40 mg q2 weeks). Disease activity responded favorably
• One a year ago, dosage reduced to 40 mg/3 weeks.
• Now, flaring again for last 6 months. DAS 5.8. Elevated ESR, positive CRP.
Case Study 1
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Low drug, Intermediate Anti-Drug Antibodies (ADAbs)
Early Immunogenicity
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No drug, Very high titer ADAbs
Late, refractory Immunogenicity
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• 48 y/o male with 3-year history of RA. Treated with methotrexate and NSAIDs
• Now presents persistent bilateral symmetric pain in wrists, knees, ankles.
• Was started on adalimumab(40 mg q2 weeks)
• Now 6 months later, no change in DAS, still positive CRP, ESR, polyarthritis
Case Study 2
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Low drug, No anti-drug antibodies
Pharmacokinetic Insufficiency
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Pharmacokinetic Variability of Biologics
One Size Fits All does not work
Up to one third of patients may be subtherapeutic.
Male genderLarger body size (BMI)Low serum albuminHigh CRP High TNF or inflammatory burden Absence of immunomodulatorPresence of ADAbs
Standard dose or dosing by weight
1. Mulleman D, et al. Infliximab concentration monitoring improves the control of disease activity in RA Arthritis Research & Therapy 2009, 11:R1782. Pouw MR et al. Adalimumab trough level in blood corresponding with clinical response Ann Rheum Dis 2013 71: 3593. Laine J et al Cost-effectiveness of routine measuring of serum drug concentrations and anti-drug antibodies in treatment of rheumatoid arthritis patients with TnF-α blockers Biologics: Targets and Therapy 2016:10 67–73
• Multiple patient-specific factors determine optimal dose• Same patient’s need may change over time
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High drug, No ADAbs
Pharmacodynamic Mismatch, non-TNF-driven disease
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TDM is Key to Right Decision-Making
1. Mulleman D, et al. Infliximab concentration monitoring improves the control of disease activity in RA Arthritis Research & Therapy 2009, 11:R1782. Pouw MR et al. Adalimumab trough level in blood corresponding with clinical response Ann Rheum Dis 2013 71: 3593. Laine J et al Cost-effectiveness of routine measuring of serum drug concentrations and anti-drug antibodies in treatment of rheumatoid arthritis patients with TnF-α blockers Biologics: Targets and Therapy 2016:10 67–73
What is the drug level?
Low
Therapeutic
What is the anti-drug
antibody titer?
Undetected
Low to Intermediate
High
No ADAbs
Increase Drug
Increase DrugMaybe add
MTx
Switch biologicIn class
Switch biologicOut of Class
Inadequate Response
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Detect total antibody not hindered by presence of drug
Anti-Drug Antibody (ADAb)
Detect free drug
Biologic Drug Concentration
Biologic Therapeutic Drug Monitoring (TDM) … Precision Medicine
• Titrate Doses for Personalized therapy1
• Identify & Prevent #1 cause of failure2-3
• Reduce drug waste3
• Manage co-therapies & drug switches 4
• Support Proactive management5
• Improve outcomes & durability of treatment5
Informs & expedites clinical decision making
1.Vande Casteele N, et al. Trough Concentrations of Infliximab Guide Dosing for Patients With Inflammatory Bowel Disease. Gastroenter 2015;148:1320-1329. 2.Ungar B, et al. The temporal evolution of antidrug antibodies in patients with inflammatory bowel disease treated with ifliximab. Gut 2014;63:1258-1264. 3.Steenholdt C, et al. Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut 2014;63:919-927. 4. American Gastroenterological Association. Guidelines for the Identification, Assessment and Initial Medical Treatment in Crohn’s Disease. https://www.gastro.org/IBDcarepathway 5. Papamichael et al. Improved Long-term Outcomes of Patients With Inflammatory Bowel Disease Receiving Proactive Compared With Reactive Monitoring of Serum Concentrations of Infliximab. Clinical Gastroenterology and Hepatology 2017;15:1580–1588 .
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• Vedolizumab and Anti-Vedolizumab Antibody, DoseASSURE™ VDZ
• Infliximab and Anti-Infliximab Antibody, DoseASSURE™ IFX
• Adalimumab and Anti-Adalimumab Antibody, DoseASSURE™ ADL
• Golimumab and Anti-Golimumab Antibody, DoseASSURE™ GOL
• Certolizumab and Anti-Certolizumab Antibody, DoseASSURE™ CTZ
• Ustekinumab and Anti-Ustekinumab Antibody, DoseASSURE™ UST
• Etanercept and Anti-Etanercept Antibody, DoseASSURE™ ETN
• Rituximab and Anti-Rituximab Antibody, DoseASSURE™ RTX
Biologic TDM…Precision Medicine
LabCorp’s DoseASSURE™is the most comprehensive biologic drug monitoring portfolio available
Inflammatory Bowel Disease
RA, Psoriasis, other related
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Rationale for Biologic TDM
1. Vaughn BP, et al. Proactive Therapeutic Concentration Monitoring of Infliximab May Improve Outcomes for Patients with Inflammatory Bowel Disease: Results from a Pilot Observational Study. Inflamm Bowel Dis 2014;20:1996-2003. 2. Steenholdt C, et al. Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut 2014;63:919-927. 3. Ordas, et al. Therapeutic Drug Monitoring of Tumor Necrosis Factor Antagonists in Inflammatory Bowel Disease. Clin Gastroenterol Hepatol 2012;10:1079-1087.
Not everyone responds. ~30%Long-term efficacy could be better.~ 50% fail at 1-2 years+ 10% every year thereafter
Clinical assessment of efficacy is
imperfect
Drug failure looks alike
despite different
underlying causes.
TDM Informs & expedites important changes in medication
The drug is expensive.
Drug failure is expensive.
The cost of the drug
>>> cost of TDM
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Biologic TDM discerns causes of failure to
1..American Gastroenterological Association. Guidelines for the Identification, Assessment and Initial Medical Treatment in Crohn’s Disease. https://www.gastro.org/IBDcarepathway
Inform & Expedite Right Action
Increase dose or shorten interval Consider switch out-of-class Evaluate Anti-Drug Antibody Titer
Low drug Positive Anti-Drug AntibodiesHigh drugLow drug
PharmacokineticNot enough drug
PharmacodynamicWrong drug
ImmunogenicAnti-drug antibodies
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What is Immunogenicity?
Anti-Drug Antibodies
1. Papamichael et al. Long-term outcome of infliximab optimization for overcoming immunogenicity in patients with inflammatory bowel disease. Dig Dis Sciences 2018;63:761-7. 2. Steenholdt C, et al. Clinical Implications of Variations in Anti-Infliximab Antibody levels in Patients with Inflammatory Bowel Disease. Inflamm Bowel Dis 2012 Vol 18 (12): 2209-2217. 3. Strik AS, van den Brink GR, Ponsioen C, et al. Suppression of anti-drug antibodies to infliximab or adalimumab with the addi- tion of an immunomodulator in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2017;45:1128–1134. 4. Ungar B, Kopylov U, Engel T, et al. Addition of an immu- nomodulator can reverse antibody formation and loss of response in patients treated with adalimumab. Aliment Pharmacol Ther. 2017;45:276–282.
• All therapeutic proteins have the potential of inducing an antibody-mediated immune response at any time
• Anti-Drug Antibodies are inversely related to drug
• ADAbs diminish drug levels, efficacy and longevity of treatment.
• ADAbs can only be diagnosed with the lab test. 30-50% of patients may develop Anti-Drug Antibodies to TNF inhibitors1
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Low titers may have little or no effect on drug levels or clinical efficacy.3
Or they may progress to higher
titers.3
High titers are likely to be more
consequential leading to loss of
drug efficacy.3
Clinicians need excellentanti-drug antibody
Tests.
Immunogenicity is #1 Reason for Loss of Response1,2
It is possible to prevent progression of immunogenicity.It is also possible to “treat away” low to intermediate titers.
1. Vincent et al. Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: a real issue, a clinical perspective Ann Rheum Dis 2013;72:165–178.2. Vermeire et al. Immunogenicity of biologics in inflammatory bowel disease Ther Adv Gastroenterol 2018, Vol. 11: 1–13. 3. Ungar et al. The temporal evolution of antidrug antibodies in patients with inflammatory bowel disease treated with infliximab. Gut 2014;63:1258–1264
How should we think of Anti-Drug Antibodies?
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Preventing drug failure & avoiding drug waste
High Performing ADAb Assay is Key
200 1000ng/mL
22 10,000+LOW HIGHINTERMEDIATE
Reversible Immunogenicity Late Refractory Immunogenicity
We designate Low, Intermediate, High
We can detect early and reliably monitor changes
Increase dose +/-Consider adding
MTX or Thiopurine
Consider switching biologics within class
(or to a different mechanism)
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Reactive TDM Proactive TDM
TDM is Key to Right Decision-Making
Determine cause of lack or loss of response Early Optimization
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Biologic TDM Informs Medication
Responder? No No No No Yes Yes YesDrug low high low - mid low low high midADAb no no low - mid high no no low
Medicationchange
Increase dose
Switch to different class
Increase dose +/- MTX or TP
Switch (in or out of class)
Optimize to target range
Prolong dosing interval
Monitor closely
Will the patientbenefit frommore drug?
YesAdd MTX?
or Thiopurine
NoDoes the patient need to switch
biologic?
Should that switch be in class?
Should it be out of class to a different
mechanism?
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Potential Checkpoints
Enables personalized dosing to achieve Early Optimization With new prescriptions Whenever re-starting biologic Before discontinuing or de-escalating biologic
Should inform & expedite medication changes in setting of failure Before switching biologic Before & after dose changes When adding second immunomodulator
Reactive TDM
Proactive TDM
Opportunity to extend duration before symptoms
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“The measurement of infliximab trough concentration modifies the therapeutic decision for RA patients and helps improve control of disease activity.”
Visit 1 Preliminary therapeutic decision • based on clinical (DAS & global)• trough collection for IFX level
24 patients on stable IFX dosage
Mulleman D, et al. Infliximab concentration monitoring improves the control of disease activity in RA Arthritis Research & Therapy 2009, 11:R178
• 7/24 (29%) were subtherapeutic.• Serum infliximab & DAS28 were inversely related.• The final therapeutic decision at Visit 2 , taking into account serum infliximab,
differed from the preliminary therapeutic decision for 50% of patients.
Two subsequent visitsVisit 2Final therapeutic decision • based on clinical plus trough IFX• 5 mcg/mL; < 2 is low; > 8 is high
Use of TDM enhanced therapeutic decisions & improved disease control
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Can TDM guide safe de-escalation of Biologic?
• L’Ami et al. Prospective 28 week Dutch study. n=147 with RA on adalimumab 40 mg q2week
• Identified 55 with serum adalimumab trough levels greater than 8 ug/mL randomized
l'Ami MJ, et al. Successful reduction of overexposure in patients with rheumatoid arthritis with high serum adalimumab concentrations: an open-label, non-inferiority, randomised clinical trial Ann Rheum Dis 2018;77:484–487. doi:10.1136/annrheumdis-2017-211781
Tapered group (n = 27) q 3 week dosing
∆DAS28 –0.14±SD 0.61 at 28 wk10.6±2.5 μg/mL to 6.6±2.0 μg/mL
Control group (n = 27) q 2 week dosing
∆DAS28 0.30±0.52 at 28 wk10.4±2.4 μg/mL to 9.3±3.0 μg/mL
Patients with adalimumab > 8 can safely prolong their dosing interval to every 3 weeks without loss of disease control (at 28 weeks)• This study demonstrates the potential benefit of TDM.• Potential cost savings of ~34%
• Tapered group did slightly better in ∆DAS28 at 28 wk, 0.44 in favor (p=0.01) • 7 (26%) versus 10 (37% control) had an increase in DAS28 ≥0.6 points after 28
weeks (p=0.56). 2 of 7 opted to return to q2wk dosing.
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How Biologic TDM optimizes Treatment
Proactive TDM may1. Improve longevity 2. Improve disease control3. Reduce complications4. Enable safe tapering
Not everyone responds.~30%
Long-term efficacy could be better.~ 50% fail at 1-2 years+ 10% every year thereafter
Reactive TDM informs when1. To continue or increase drug2. To add co-therapy3. To switch biologic4. Whether to switch biologic in- or out-of-class
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I have no actual or potential conflict of interest in relation to this program/presentation.
• Grant/Research Support: N/A• Speaker’s Bureau: N/A• Consultant: N/A• Major Shareholder: N/A• Other: N/A
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Target ranges for trough concentrations in RA
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Cost savings ranging from 28 to 34%
Cost effectiveness of Biologic TDM
Martell et al. Cost-effectiveness of drug monitoring of anti-TNF therapy in inflammatory bowel disease and rheumatoid arthritis: a systematic review J Gastroenterol (2017) 52:19–25
• Individualized therapy using an algorithm with drug and anti-drug antibody measurements leads to major cost savings related to anti-TNF therapy in both IBD and RA patients with no negative impact on efficacy.
• Sum of healthcare costs related to Crohn’s disease was substantially lower (31 %) for patients randomized to algorithm- based interventions: $11,940 versus $17,236.
• At 5 years, cost savings among the 10,000 CD patients using a test-based strategy were $152,932,672, and the mean cost saving per patient was $15,292.
• Three modeling approaches in CD demonstrated savings of $5396+ over a 1 year period.
Martelli 2017 Review : Cost Effectiveness of Biologic TDM in IBD and RA
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Infliximab• In rheumatoid arthritis, EULAR responders had higher trough levels (median
3.6 ug/mL) than non-responders (0.5 ug/mL). Wolbink et al. Relationship between serum trough infliximab levels, pretreatment C reactive protein levels, and clinical response to infliximab treatment in patients with rheumatoid arthritis. Ann Rheum Dis 2005;64:704–707.
Adalimumab• In rheumatoid arthritis, trough levels of 5 to 8 ug/mL are associated with
clinical response (EULAR).• Patients with higher levels did better, up to about 12.
Pouw et al. Key findings towards optimising adalimumab treatment: the concentration–effect curve. Ann Rheum Dis 2015;74:513–518.Pouw et al. Adalimumab trough level in blood corresponding with clinical response. Ann Rheum Dis 2013 71: 359
Target Ranges & Maximally Beneficial Concentrations
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Etanercept• In rheumatoid arthritis (RA), good responders had higher trough levels
(median 3.8 ug/mL, 2.5 – 5.2) than non-responders (2.8 ug/mL, 1.3 - 3.9).
• Trough concentrations > 3.1 ug/mL at 3 months predict EULAR response to etanercept at 6 months.
Jamnitski et al. Patients non-responding to etanercept obtain lower etanercept concentrations compared with responding patients. Ann Rheum Dis 2012;71:88–91. Daien et al. Etanercept Concentration in Patients with Rheumatoid Arthritis and Its Potential Influence on Treatment Decisions: A Pilot Study. J Rheumatol 2012;39;1533-1538
Certolizumab• In rheumatoid arthritis, higher drug levels (> 23 ug/mL) are associated
with better 12 month EULAR response.• 37% incidence of anti-certolizumab antibodies in RA over 12 months.
Jani M et al. AnnRheum Dis 2017;76:208-213
Threshold concentrations may predict response
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Ustekinumab• In plaque psoriasis, median trough ustekinumab concentrations were 0.4 ug/mL
at weeks 14 and 28 (ranging from undetectable to 3.6 ug/mL).• Responders (PASI 50) had higher trough concentrations (median 0.3 ug/mL)
than non-responders (0.07 ug/mL, p= 0.03) in a study of 76 patients• A definitive therapeutic target range for psoriasis has yet to be established.
Golimumab• In rheumatoid arthritis, higher trough levels (median 3.4 ug/mL)
correspond to a greater rate of clinical responseKay et al. Golimumab in Patients with Active Rheumatoid Arthritis Despite Treatment with Methotrexate. Arthritis Rheum 2008;58(4):964975.
Efficacy is Concentration-Dependent
Menting SP, Coussens E, Pouw MF, et al. Developing a therapeutic range of adalimumab serum concentrations in management of psoriasis: a step toward personalized treatment. JAMA Dermatol. 2015;151(6):616–622.
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